WCD 2023 congress highlights on alopecia areata

The changing landscape and new molecules for the treatment of alopecia areata

By Veena Angle

The 25^th World Congress of Dermatology 2023 was held in Singapore from 3–8 July. This article is the first in a series of three covering discussions on the management of alopecia areata (AA) at the congress.

New therapeutic options and strategies

Until last year, systemic corticosteroids, cyclosporine, and methotrexate were the mainstay of treatment paradigms in moderate to severe alopecia. The landscape has changed since last year, with two Janus Kinase (JAK) inhibitors baricitinib and ritlecitinib approved by the FDA for treating moderate to severe AA. Subject to the accessibility of the new therapies, patients with moderate AA can be treated with JAK inhibitors and other systemic immunotherapies. In severe AA, JAK inhibitors have replaced conventional treatments with or without oral minoxidil and intralesional corticosteroids. Other systemic immunotherapies may be used with or without oral minoxidil and intralesional corticosteroids as a second line of treatment.

Dr Ruaa Al Harithy of the Dermatology Department, Security Forces Hospital, Riyadh, Saudi Arabia emphasized the ineffectiveness of topical and sublingual administration of JAK inhibitors in treating AA based on clinical studies¹. A meta-analysis (PROSPERO: CRD 42022303007) comparing baricitinib, ritlecitinib, and brepocitinib showed similar efficacy and tolerability for oral JAK inhibitors in treating AA, whereas topical or sublingual administration lacked efficacy². Currently, the clinical decision on using JAK inhibitors is primarily dictated by FDA approval, cost and accessibility of the drugs.

Dr Jerry Shapiro, Professor of Dermatology at New York University School of Medicine in the United States, also supported using JAK inhibitors in severe AA, and switching from tofacitinib to baricitinib³. Tofacitinib has been approved for use in rheumatoid arthritis but is frequently used off-label in treating alopecia⁴.

In 2022 and 2023, the FDA approved the first systemic therapies for AA, both JAK inhibitors

Data from pivotal trials of JAK inhibitors

Baricitinib was the first JAK inhibitor approved by the FDA for adults with severe AA in June 2022⁵. It is the first systemic therapy approved for use in AA, thus extending treatment to the entire body rather than specific areas. The FDA approval for baricitinib is supported by efficacy and safety data from two phase 3 randomised controlled trials (BRAVE-AA1 and BRAVE-AA2) in patients with a Severity of Alopecia Tool (SALT) score of 50 or higher⁶.

On 23 June 2023, the FDA approved the second JAK inhibitor, ritlecitinib, for severe AA in adults and adolescents (≥12 years) based on the phase 2b/3 ALLEGRO trial results. The ALLEGRO trial showed an acceptable safety profile and efficacy for ritlecitinib up to 48 weeks in patients aged 12 years and over with at least 50% scalp hair loss⁷. Efficacy was also observed in the regrowth of eyebrows and eyelashes, which are otherwise difficult to treat¹.

Dr Melissa Piliang, Dermatologist at the Cleveland Clinic in the United States, presented a late-breaker session on the long-term efficacy of ritlecitinib up to 24 months in an integrated analysis of the ALLEGRO phase 2b/3 and long-term phase 3 clinical studies in alopecia areata (ALLEGRO-LT/NCT04006457)⁸. Patients rolled over from the ALLEGRO-2b/3 trial and de novo patients receiving ritlecitinib 50 mg (with or without 200 mg loading dose) demonstrated clinically meaningful and sustained long-term clinician and patient-reported efficacy through month 24.

Safety of JAK inhibitors and FDA black box warning

The FDA issued a black box warning about the increased risk of heart-related severe events, cancer, blood clots and death with JAK-inhibitors used to treat chronic inflammatory conditions last year. However, experts at WCD 2023 were sceptical of the warning in relation to the treatment of AA⁹. Dr Al Harithy highlighted that the black box warning was issued based on major cardiovascular adverse events (MACE) and malignancies in patients with rheumatoid arthritis who were aged 50 years or older with at least one cardiovascular (CV) risk factor^1,10, in contrast to AA patients who are typically younger and without CV risk. Dr Sergio Vano-Galvan, Head of the Trichology Unit at Ramón y Cajal Hospital, Madrid, also shared that serious adverse events were rare in patients with AA treated with JAK inhibitors¹¹.

Regardless, Dr Shapiro highlighted the importance of selecting suitable candidates for therapy with JAK inhibitors and monitoring patients during treatment with laboratory tests³. Treatment should not be initiated in case of abnormalities in the blood counts and liver enzymes. Good candidates for treatment of AA with JAK inhibitors are patients aged 18-50 years with no comorbidities, SALT scores of more than 50 and the current episode lasting for less than 5 years with active disease.

While positive clinical trial results and long-term data form the basis for recent approvals of JAK inhibitors for treating alopecia areata, it is important to choose patients suitable for these therapies

JAK inhibitors for alopecia areata: From bench to bedside and beyond

By Veena Angle

The 25^th World Congress of Dermatology 2023 was held in Singapore, from 3-8 July. This is the second in a series of three articles covering discussion related to the management of alopecia areata (AA) at the congress.

Dr Alessandra Anzai, University of Sao Paulo, Brazil, documented the journey of immunotherapies in AA from the bench to the bedside¹². Early genome-wide association studies identified innate and adaptive immunity as contributing to AA pathology¹³. Subsequent research stimulated development of the first systemic treatment for AA, with the JAK inhibitor baricitinib being approved by the US FDA in 2022. AA is treatable through inhibiting the JAK 1 and/or 3 pathways.

Dr Sergio Vano-Galvan, Head of the Trichology Unit at Ramón y Cajal Hospital, Madrid, presented on novel therapeutic approaches in AA. “A new era has arrived in alopecia areata with the use of JAK inhibitors,” said Dr Vano-Galvan referring to US FDA and EMA approvals for baricitinib in treating severe AA¹⁴. For severe AA, American guidelines propose JAK inhibitors as first-line treatment¹⁵. Given the results observed in his patients, Vano-Galvan expects JAK inhibitors to become a standard-of-care for the treatment of AA.

The US FDA has approved baricitinib (JAK 1/2) and ritlecitinib (JAK 3) for the treatment of AA. Ritlecitinib is expected to receive EMA approval in late 2023; deu-ruxolitinib (JAK 1/2) is predicted to be approved by the FDA and EMA in 2024¹¹.

Areas in AA that warrant further studies include:

• Gut microbiota can impact on immunoregulation in autoimmune diseases such as AA; fecal microbial transplantation could be a treatment option for AA¹⁶
• Genetic abnormalities, resulting in abnormalities of the hair follicle, may predispose certain people to develop AA¹⁷

Conclusions from clinical studies on JAK inhibitors for alopecia areata

Clinical trials demonstrate that more than one-third of patients with AA on baricitinib can achieve ≥80% hair regrowth¹⁸. Up to 40% of patients with AA on ritlecitinib can achieve ≥80% hair regrowth¹⁹.

On the safety profile of the JAK inhibitors, Dr Vano-Galvan emphasised that the serious adverse events mentioned in the black box warning were not frequently observed in patients with AA. In his clinical experience, adverse events observed following use of JAK inhibitors in AA tend to be mild, and included upper respiratory tract infections, headaches, nasopharyngitis, nausea and acne¹¹.

On baricitinib trials, Dr Vanos-Galvan made these observations¹¹:

• A higher proportion of patients with severe AA compared to very severe AA achieved SALT score ≤20 after 36 weeks, indicating that disease severity may influence the prognosis and time to response on baricitinib
• Baricitinib significantly improved the response rate in patients with SALT ≤20, regardless of the duration of the current episode
• After 52 weeks, achievement of meaningful improvement in eyebrow and eyelash regrowth occurred across all response subgroups (including those who did not respond with growth in scalp hair), with greater response rates in patients with SALT score ≤20
• Almost 40% of partial responders after 52 weeks can achieve clinically meaningful scalp hair regrowth at 104 weeks if treatment is continued
• There is no loss in the efficacy of baricitinib over time, with approximately 90% of patients who responded at 52 weeks being able to maintain clinically meaningful scalp hair regrowth through to one-hundred and four weeks
• Down titration of baricitinib in patients with severe AA is likely to cause a relapse

Dr Anzai interpreted clinical trial data on JAK inhibitors for AA as follows¹²:

• Oral formulations of JAK inhibitors are more effective than placebo, whereas topical formulations are less effective
• There is no significant difference in the efficacies of baricitinib, ritlecitinib and brepocitinib in clinical trials
• There is no significant difference in efficacy of ruxolitinib and tofacitinib in non-randomised clinical trials
• An equal proportion of patients treated with JAK inhibitors show complete response, partial response, or no response
• The response time for treatment of AA with JAK inhibitors can take 6–12 months
• Relapse is common after discontinuation of JAK inhibitors
• Long-term maintenance therapy raises concerns of side effects and toxicity

Strategies to improve therapy effectiveness for alopecia areata

Dr Vano-Galvin shared his positive experience with novel therapies in the AA setting, including imiquimod as an enhancer of immunotherapy with diphencyprone²⁰, oral mini-pulses of dexamethasone (0.1 mg/kg per day for two consecutive days each week), a combination of oral dexamethasone and topical diphencyprone, corticosteroid injections in the hair bulb, and oral etrasimod¹¹.

Dr Vano-Galvan expressed disappointment with the results of the phase 2 trial of dupilumab (monoclonal antibody targeting IL4 and IL13) in AA. After 48 weeks of dupilumab treatment, 32.5%, 22.5% and 15% achieved SALT30, SALT50 and SALT75, respectively. Baseline IgE >200 IU/ml levels may serve as biomarkers for a positive response to treatment²¹.

A novel and promising agent, LH-8, is being investigated in a placebo-controlled phase 2/3 clinical trial in patients aged 2–18 years²².

Strategies that can increase the efficacy of JAK inhibitors for AA include increasing treatment dose, or combination therapy comprising JAK inhibitors with methotrexate or corticosteroids, oral minoxidil, or clarithromycin. In case of poor patient response, switching between JAK inhibitors with different pathways can be an option¹². For example, in patients with AA who partially respond or experience a recurrence of hair loss after an initial favorable response to tofacitinib therapy can benefit from switching to baricitinib²³.

From registration trials to combinations and novel therapies, the treatment armamentarium for alopecia is growing

Clinical trial and real-world data on managing alopecia areata

By Veena Angle

The 25^th World Congress of Dermatology 2023 was held in Singapore, from 3–8 July. This is the third in a series of three articles covering discussion related to the management of alopecia areata (AA) at the congress.

New data from BRAVE-AA1, BRAVE-AA2, ALLEGRO-LT

Assistant Professor Maryanne M Senna from the Lahey Hospital and Medical Center, Harvard Medical School, Boston, United States, presented patient-reported outcomes (PRO) from the phase 3 clinical trials, BRAVE-AA1 (NCT03570749) and BRAVE-AA2 (NCT03899259) for scalp, eyebrow, and eyelash, in patients with severe AA treated with baricitinib.

• There was continuous improvement in scalp, eyebrow and eyelash PROs over 52 weeks
• For eyelash hair regrowth, response rates were 24.3% for baricitinib 2 mg, and 40.8% for baricitinib 4 mg
• For eyebrow hair regrowth, response rates for baricitinib 2 mg and 4 mg were 21.3% and 40.4%, respectively

These results are significant for patients more concerned about the cultural significance of facial hair than scalp hair loss²⁴.

Associate Professor Brett King from Yale School of Medicine, New Haven, United States, presented post hoc analyses from BRAVE-AA1/2 for duration of hair loss and clinically meaningful hair regrowth. There was a trend toward better treatment response in patients with a shorter duration of hair loss, regardless of baseline disease severity. Thus, early intervention may confer greater treatment efficacy for patients with severe AA treated with baricitinib²⁵.

Professor Rodney Sinclair of the Department of Medicine, University of Melbourne, Australia, presented interim results from the ALLEGRO-LT phase 3 study evaluating the long-term safety and efficacy of ritlecitinib in patients with AA up to month 36. The study included patients over 12 years of age with ≥25% hair loss rolled over from the ALLEGRO phase 2a and 2b/3 studies, and patients who had not participated in either study. At data cutoff, 78.3% of patients reported adverse events (AE) that were mild or moderate in severity. The most frequent treatment emergent AEs were headache (16.3%), acne (11.6%), nasopharyngitis (8.5%), SARS-CoV-2 test positive (13.4%), and urticaria (8.1%). Rates of serious AEs, severe AEs, and treatment discontinuations were 4.0%, 5.4%, and 4.9%, respectively. At month 24, 69.6% achieved SALT scores of ≤20, 62.5% of patients had SALT scores of ≤10. Regrowth of eyebrow and eyelash hair was observed in 54.1% and 63.9% of patients, respectively²⁶.

Phase 3 clinical trials of different treatment options for alopecia are also considering impact on patient wellbeing and other patient-reported outcomes

Research on treating alopecia areata in routine clinical practice

The abstracts and free communications sessions were an opportunity for dermatologists to describe their experiences managing AA in routine clinical practice. Therapies for managing patients with AA were presented, including apremilast²⁷ and low-dose oral minoxidil²⁸, which are options in settings with limited access to approved drugs.

Dr Yuping Tan of the Department of Dermatovenereology, West China Hospital, Sichuan University, presented an analysis of treatment with baricitinib in his patients with AA conducted over 1.5 years. Patients were treated with glycyrrhizin and/or diprosone intramuscular injection combined with 2% or 5% minoxidil tincture, and oral baricitinib 2/4 mg. Hair regrowth was visible after 2 months in 41.3% of patients and by week 24, 35% of the patients achieved 80% hair regeneration. AEs were mild and did not warrant discontinuation of treatment²⁹.

Dr Huw Rees of Sinclair Dermatology, Melbourne, Australia, presented data from the pilot phase of the Global Registry of Alopecia Areata Disease Severity and Treatment Safety (GRASS). The registry is an international collaborative network of patient registries collecting harmonised epidemiological, socioeconomic and treatment data. Currently, national registries have been established in Australia, Italy, and Ireland. The registry enrolled 489 patients in the first six months, who had a median SALT score of 20 (IQR = 86.5%). Scalp involvement was reported in 78.5% (95% CI 71.9–83.9). Most had patchy AA (59.3%; 95% CI 52.0–66.3), while 7.7% (95% CI 4.4–12.4) and 16.0% (11.1–21.9) had alopecia totalis or alopecia universalis, respectively. The group is seeking interest from dermatologists from across the globe, aiming to recruit diverse ethnic populations³⁰.

The results of longer-term treatment show that hair regrowth continues to improve for adults with severe alopecia areata on baricitinib